BB2121

BB2121

The Science

BB2121 is an anti-BCMA chimeric antigen receptor (CAR) T-cell therapy currently being investigated by Celgene and Bluebird Bio to primarily treat Multiple Myeloma patients.
Multiple Myeloma cells express B-Cell Maturation Antigen (BCMA) on their surface, BB2121 is a T cell that has been engineered to add the chimeric antigen receptor protein that is specific to BCMA.

BCMA is a cell surface protein that is involved in the differentiation and maturation of B-cells into plasma cells. BCMA is very common on Myeloma and plasma cells but is under expressed on B Lymphocytes, meaning it is a promising target for investigational treatments.

The receptor is chimeric as it combines antigen-binding and T-cell activating functions into a single receptor. BB2121 has two intracellular domains, one involved in signalling and one to increase the proliferation, persistence and activation of the T cell.

T-cells (or Lymphocytes) are produced by the immune system and are part of the bodies immune response to antigens that does not involve producing antibodies but rather engulfing or producing cytokines to kill the pathogen.

CAR T-cells are made from the patient’s own T-cells.  A sample of the patient’s white blood cells is collected, and T-cells are genetically modified in the laboratory to recognise BCMA found on the surface of Myeloma cells. The T-cells are then grown to very high numbers and reintroduced into the patient’s body.

BB2121 cells are thus designed to bind to Multiple Myeloma cells and apoptose them without affecting the bodies own immune cells.

The Upside

BB2121's main focus has been for Multiple Myeloma and there are currently 5 studies investigating its effects (sometimes in combination with other treatments). 

Data from the Phase I CRB-401 trial showed bb2121 was associated with a 95.5% overall response rate after 194 days. Moreover, it induced a progression-free survival (PFS) of 11.8 months, with a median duration of response of 10.8 months. We need to keep in mind that the patients in the study were heavily pre-treated, with a median of seven prior regimens for treating multiple myeloma. But nonetheless the fact that we're seeing a PFS of close to 1 year in this heavily pretreated patient population with more than 7 prior lines of treatment is quite incredible. 

BB2121 was found to be extremely well tolerated in patients. Cytokine Release Syndrome was seen in roughly 60% of patients, but this was mostly grade 1 and 2 (low). After assessment of the dose escalation trial, the treatment was designated breakthrough therapy status. 

Celgene and Bluebird are working in collaboration on a study currently in Phase III that is due to report results in 2019. The global Multiple Myeloma market was valued at $7.5 Billion in 2015 and is predicted to grow to to a value of $37.5 Billion in 2024, a CAGR of about 20%.

Cannaccord's John Newman has forecasted blockbuster annual sales for BB2121 at roughly $2 Billion if it is approved. Lets say BB2121 was approved in 2019 and hit these sales targets in 2022. The drug could be worth almost $3 Billion in annual sales in 2024 commanding a 8% market share. 

The Downside

Realistically it would be hard for a new drug to command a share >10% of the entire market for a certain condition. Especially if there were competitors that worked just as well. 

Amgen is a competing company that currently has a treatment in the pipeline for Myeloma, AMG-420.  This therapy is currently in earlier phases of trials however has shown better prognostic indicators for patient survival and treatment efficacy.

Each patient treated with BB2121 had to have their T-cells removed, then shipped to a manufacturing site where they're trained to express a chimeric antigen receptor (CAR-T) that recognises B-cell maturation antigen (BCMA), which is usually found on cancerous plasma cells.

Manufacturing a new batch for each patient is very time consuming and expensive and isn't the only challenge CAR-T therapies face. Before starting CAR-T therapy, patients need to hang around a hospital for at least a few days while nurses kindly wipe out their immune systems with lymphodepleting chemotherapy.

AMG-420 is part of a drug class called bi-specific T-cell engagers (BiTEs), which are just two-sided proteins that can be taken off a shelf and plugged into a patient's IV drip. Despite being easier to manufacture, warehouse, and administer to patients, AMG-420 accomplishes the same complex task as bb2121 by clinging to BCMA with one arm, while the opposite side engages T-cells and holds them in place until they cause the cancerous cell to burst. BCMA has been toted a very attractive new target for cancer therapies.

More on AMG-420 to come. 

Finally, as BB2121 is being developed in collaboration with Celgene, Bluebird bio is eligible to receive specified development, regulatory and commercial milestone payments and royalty payments on net sales.

The Conclusion

BB2121 may get to the market faster and may be adopted by physicians due to its high PFS and RR numbers at first. However the process for producing a CAR-T therapy is very time consuming, expensive and debilitating for patients. Thus when/if a new therapy such as AMG-420 comes to market, I believe it could quickly overtake BB2121 in the line of treatment.

I would not expect a large increase in share price of the combined entity of Celgene/BMS if approved. Combined sales are expected to be somewhere in the region of $45 Billion, so the $2 Billion expected for BB2121 is really a drop in the ocean. My estimate would be a 3-4% share price rise. 

Celgene already have a couple of drugs for Myeloma and I do not believe BB2121 is revolutionary enough to persuade share holders that it will overtake Revlimid, Pomalyst etc in sales. The advantage for approval of BB2121 is a step towards the CVR that has been agreed for Celgene Shareholders, in which they will receive $9 per share if BB2121, Liso-Cel and Ozanimod are approved by the FDA within the preset timelines (2019-2021). 

-OC


Disclaimer:
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company who is mentioned in this article. This article is not investment advice, and can't be relied upon by anyone for any reason except, arguably, entertainment purposes. I am not an investment advisor.

https://www.grandviewresearch.com/press-release/global-multiple-myeloma-therapeutics-market

https://pharmaphorum.com/news/bluebird-bio-aims/

https://seer.cancer.gov/statfacts/html/mulmy.html

https://immuno-oncologynews.com/bb2121/

https://www.targetedonc.com/news/expert-reflects-on-incredible-data-seen-with-bb2121-in-heavily-pretreated-myeloma

https://clinicaltrials.gov/ct2/show/NCT03651128?term=BB2121&phase=2&rank=1

https://www.onclive.com/conference-coverage/asco-2018/bb2121-adds-nearly-1-year-of-pfs-for-heavily-pretreated-myeloma